Despite advances in chemoradiation therapy, the 5-year survival rate from esophageal squamous cell cancer (SCC) remains a dismal 15% due to diagnosis at a late, incurable stage. Endoscopic screening is typically performed in high-risk populations with Lugol's iodine staining of the mucosa and targeted biopsy of abnormal (unstained) areas. While Lugol's significantly increases the sensitivity of standard white-light endoscopy, specificity remains poor as inflammation and other benign mucosal changes can mimic neoplasia. While high-resolution imaging with confocal endomicroscopy has been shown to dramatically enhance the diagnostic accuracy and yield of Lugol's chromoendoscopy and other widefield techniques, existing platforms are costly (>$150,000) and only available in a handful of tertiary centers worldwide. Our group has developed a low-cost, portable, battery-operated high-resolution microendoscope (HRME) that can provide subcellular images of the esophageal epithelium and delineate the cellular and morphologic changes associated with neoplasia. Our central hypothesis is that this low-cost imaging device will increase the efficiency and yield of current endoscopic screening practices by offering a real-time, in vivo diagnosis ('optical biopsy') in clinically indeterminate areas. This will allow for more selective (i.e. targeted) biopsies and will offer the potential for immediate clinical decision- making. To determine this, we will conduct a clinical trial of the device in high-risk subjects undergoing endoscopic screening for suspected squamous cell neoplasia in both the United States and northern China. Specifically, we will determine (a) the diagnostic accuracy (sensitivity and specificity) of the HRME for the in vivo diagnosis of esophageal squamous neoplasia, and (b) the diagnostic yield and potential clinical impact of the HRME in this population. Successful results can easily be translated to other organ systems (skin, colon, cervix, etc.). PUBLIC HEALTH RELEVANCE: Esophageal cancer is a major global health problem and carries a poor prognosis when diagnosed at a late stage. The improved identification of early neoplasia offers the greatest opportunity to reduce morbidity and mortality worldwide.